Among the several plausible neuropathological hypotheses underlying the progression of aging and neurodegenerative diseases such as Parkinson’s disease (PD), oxidative stress and mitochondrial damage have emerged as one of the attractive biochemical mechanisms. However, most of the past studies linking mitochondrial dysfunction to neuronal degeneration have been carried out in vitro or in acute in vivo studies. It is not known whether mitochondrial dysfunction is an immediate response to cytotoxic-inducing agents or is sustained as a long-term consequence of neuronal death. The purpose of our research was to first validate the chronic mouse model of Parkinson’s disorder (MPD), which has been developed and characterized by our laboratory as a suitable animal model for investigating neuronal and mitochondrial dysfunctions and then to examine the protective effects of endurance exercise and melatonin treatment on this model.
Male, C57/BL retired breeder mice at 6-10 months of age were used in the present study. The aged chronic MPD was treated with of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (15 mg/kg, s.c), twice a week for 5 weeks. MPTP was co-administered with probenecid (250 mg/kg, i.p), an adjuvant that is known to inhibit the peripheral and neuronal clearance of MPTP and potentiate the neurotoxicity of MPTP. The chronic MPD was previously shown to display neurochemical, histological, behavioral and pathological features resembling those of PD-like neurodegeneration lasting for at least 6 months.
Six to twelve weeks after chronic MPTP treatment, aged mice showed sustained decrease in striatal mitochondrial respiration as well as loss of antioxidant enzymes, Cu-Zn superoxide dismutase (SOD), Mn SOD and cytochrome c (cyt c) expression. Striatal mitochondrial dysfunction correlated with dopamine neuron and behavioral deficits in the aged chronic MPD. When the chronic MPD was exercise-trained on a motorized treadmill 5 days/week for 18 weeks, the dopamine neuronal, mitochondrial and behavioral deficits as seen in the sedentary chronic MPD were prevented.
Melatonin (5 mg/kg, i.p), a known natural antioxidant and free radical scavenger was injected to the chronic MPD 5 days/week for 18 weeks. Melatonin alone did not alter the striatal neuronal, mitochondrial and motor functions in normal mice. However, melatonin was effective to reverse dopaminergic, mitochondrial and motor impairment as exercise did to the chronic MPD. We conclude that endurance exercise training and melatonin treatment are effective neuroprotective and mitochondrial protective measures in the chronic MPD. Exercise and melatonin treatment may have the potential to slow the progression of PD related neurodegeneration.